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To investigate the possibility that rhythmic activity originating in the central nervous system may modulate human eye movements, anticipatory eye movements were generated by tracking an intermittently obscured sinusoidally moving target. Eight subjects tracked intermittently obscured sinusoids of three different frequencies and of two different amplitudes. Eye movements were recorded by an infra-red reflection technique. The eye velocity records were analysed in the frequency domain by power spectral estimates. During periods where the target was obscured, eye movements consisted of a staggered series of anticipatory saccades with intervening smooth anticipatory eye movements or relatively stationary periods. In sections where the intervening smooth components of anticipatory tracking were of high velocity (above 15 deg/s), a superimposed smooth tremulous oscillation at around 10 Hz was sometimes present. Coherence analysis showed that this 10 Hz range oscillation of smooth anticipatory movement was not derived from head tremor and that the same oscillation was present in both eyes. This oscillation was not generally observed during smooth tracking of pseudorandom waveforms. Investigation of anticipatory eye movements has revealed a 10-Hz range oscillation or "tremor" superimposed upon smooth movements that might in other circumstances be inhibited by direct visual feedback. This smooth eye movement oscillation is thought to originate from the central nervous system and may reflect a widespread frequency modulation of motor commands.

Susceptibility to develop Parkinson's disease has been linked to abnormalities of P450 enzyme function. Multiple P450 enzymes are expressed in brain but the relationship of these to Parkinson's disease is unknown. We have investigated the expression of P450 enzymes in the rat substantia nigra and their co-localization in tyrosine hydroxylase-positive neurons and astrocytes. Immunohistochemistry was performed using anti-peptide antisera against the following P450 enzymes: CYP1A1, CYP1A2, CYP2B1/2, CYP2C12, CYP2C13/2C6, CYP2D1, CYP2D4, CYP2E1, CYP3A1, CYP3A2 and NADPH-P450 oxidoreductase. Immunoreactivity in nigral cells was found only for CYP2E1 and CYP2C13/2C6. CYP2E1 immunoreactivity was localized to many midbrain nuclei including the substantia nigra pars compacta but not the substantia nigra pars reticulata while immunoreactivity to CYP2C13/2C6 was found in the substantia nigra pars compacta, substantia nigra pars reticulata and many other midbrain nuclei. Sections of rat midbrain double labelled for either CYP2E1 or CYP2C13/2C6 and tyrosine hydroxylase or glial fibrillary acidic protein were examined for co-localization by confocal laser scanning microscopy. CYP2E1 and CYP2C13/2C6 immunoreactivity was found in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta but not in glial cells. CYP2C13/2C6, but not CYP2E1, was also found in non-glial, non-tyrosine hydroxylase-expressing cells in the substantia nigra pars reticulata. Isoniazid induction increased CYP2E1 fluorescence signal intensity from nigral dopaminergic neurons. At least two P450 enzymes are found in nigral dopamine containing cells and one, namely CYP2E1, is selectively localized to this cell population. CYP2E1 is a potent generator of free radicals which may contribute to nigral pathology in Parkinson's disease. The expression of CYP2E1 in dopaminergic neurons in substantia nigra raises the possibility of a causal association with Parkinson's disease.

The cause of neuronal loss in patients with idiopathic Parkinson's disease is unknown. Oxidative stress and complex I deficiency have both been identified in the substantia nigra in Parkinson's disease but their place in the sequence of events resulting in dopaminergic cell death is uncertain. We have analysed respiratory chain activity, iron and reduced glutathione concentrations in Parkinson's disease substantia innominata and in the cingulate cortex of patients with Parkinson's disease, Alzheimer's disease and dementia with Lewy bodies to investigate their association with neuronal death and Lewy body formation. No abnormalities of mitochondrial function, iron or reduced glutathione levels were identified in Parkinson's disease substantia innominata or cingulate cortex. Mitochondrial function also appeared to be unchanged in cingulate cortex from patients with Alzheimer's disease and from patients with dementia with Lewy bodies, however, iron concentrations were mildly increased in both, and reduced glutathione decreased only in Alzheimer's disease. These results confirm the anatomic specificity of the complex I deficiency and decreased levels of reduced glutathione within the Parkinson's disease brain and suggest that these parameters are not associated with cholinergic cell loss in Parkinson's disease nor with Lewy body formation in this or other diseases. We propose that our data support a 'two-hit' hypothesis for the cause of neuronal death in Parkinson's disease.

Expression of glutamate decarboxylase-67 messenger RNA was examined in the basal ganglia of normal controls and of cases of Parkinson's disease using in situ hybridization histochemistry in human post mortem material. In controls glutamate decarboxylase-67 messenger RNA expression was detected in all large neurons in both segments of the globus pallidus and in three neuronal subpopulations in the striatum as well as in substantia nigra reticulata neurons and in a small sub-population of subthalamic neurons. In Parkinson's disease, there was a statistically significant decrease of 50.7% in glutamate decarboxylase-67 messenger RNA expression per neuron in the lateral segment of the globus pallidus (controls: mean 72.8 microns2 +/- S.E.M. 8.7 of silver grain/neuron, n = 12; Parkinson's disease: mean 35.9 microns2 +/- S.E.M. 9.7 of silver grain/neuron, n = 9, P = 0.01, Student's t-test). In the medial segment of the globus pallidus, there was a small, but non-significant decrease of glutamate decarboxylase-67 messenger RNA expression in Parkinson's disease (controls: mean 100.6 microns2 +/- S.E.M. 7.2 of silver grain/neuron, n = 11; Parkinson's disease: mean 84.8 microns2 +/- S.E.M. 13.0 of silver grain/neuron, n = 7, P = 0.1, Student's t-test). No significant differences in glutamate decarboxylase-67 messenger RNA were detected in striatal neuronal sub-populations between Parkinson's disease cases and controls. These results are the first direct evidence in humans that there is increased inhibitory drive to the lateral segment of the globus pallidus in Parkinson's disease, as suggested by data from animal models. We therefore provide theoretical support for current experimental neurosurgical approaches to Parkinson's disease.

GTP cyclohydrolase I (GTPCH) has recently been identified as the first causative gene for Dopa-responsive dystonia (DRD). DRD typically presents with dystonia in the lower limbs in childhood, but may produce an akinetic-rigid syndrome in middle and old age. We have sequenced the GTPCH gene in 29 Parkinsonian patients without a positive family history for DRD, but who shared at least one feature of the akinetic-rigid presentation of DRD: 23 patients had at least one living relative who also suffered from an akinetic-rigid syndrome; 2 patients had an abnormally mild course of their parkinsonism which was extremely dopa-responsive. DNA was also analysed from 4 brain samples of patients who were clinically diagnosed as suffering from Parkinson's disease, but then did not show any pathological findings at post mortem. No changes in the sequence of the GTPCH gene were detected. We conclude that so far there is no evidence that mutations of the GTPCH gene are responsible for the development of parkinsonism in patients without a positive family history of DRD.

Basic fibroblast growth factor (bFGF) promotes the survival and growth of dopaminergic neurons. We have investigated the effect of treating fetal ventral mesencephalon with bFGF or nerve growth factor (NGF) on the subsequent survival and function of grafted dopaminergic neurons implanted into the striatum of rats with a unilateral 6-hydroxydopamine lesion. Animals implanted with fetal ventral mesencephalon mixed with bFGF, but not with NGF, displayed more rapid compensation in motor behavior up to 9 weeks after graft implantation. bFGF, but not NGF, produced an increase in the number of tyrosine hydroxylase (TH)-positive neurons, a larger graft volume, and longer neurite outgrowth in comparison to control grafts. bFGF also increased the number of glial fibrillary acidic protein (GFAP)-positive astrocytes within the grafts. The increased number of GFAP-positive astrocytes induced by bFGF correlated with the increase in the number of TR-positive neurons, with graft volume and with neurite outgrowth. These findings support the use of bFGF to promote the functional integration of fetal ventral mesencephalon grafts into the denervated host brain and and suggest that its action may be indirectly mediated through glial cells.

Nigral cell death in Parkinson's disease is associated with decreased reduced glutathione (GSH) levels, impaired complex I activity and inhibition of alpha-ketoglutarate dehydrogenase (alpha-KGDH) in substantia nigra. Thioctic acid exerts antioxidant activity through a thiol-disulphide redox couple and is an essential cofactor for alpha-KGDH. However, it is not known whether or not thioctic acid enters basal ganglia or exerts beneficial effects in Parkinson's disease. As a global measure of altered cerebral function, the effect of R- and S-thioctic acid on 14C-2-deoxyglucose (14C-2DG) incorporation was investigated in rats. Rats were treated with either R- or S-thioctic acid (50 mg/kg IP) or 0.9% saline acutely or for 5 days and 14C-2DG incorporation in basal ganglia was assessed. Following acute administration, R- but not S-thioctic acid caused an overall increase in 14C-2DG incorporation that was significant in both substantia nigra zona compacta and zona reticulata. R-thioctic acid also increased the incorporation of 14C-2DG in the medial forebrain bundle, thalamus, and red nucleus. S-thioctic acid decreased 14C-2DG incorporation in the subthalamic nucleus, but increased it in the red nucleus. Following repeated administration, R-thioctic acid no longer increased 14C-2DG incorporation in either zona compacta or zona reticulata of substantia nigra. However, both R- and S-thioctic acid now decreased 14C-2DG incorporation in the subthalamic nucleus. The data suggest that thioctic acid does enter the brain can alter neuronal activity in areas of the basal ganglia intimately associated with the motor deficits exhibited in Parkinson's disease.

Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurodegenerative process underlying nigral cell death in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be inhibitors of complex I, and have been implicated in the cause of PD as endogenous neurotoxins. To determine the potency and structural requirements of isoquinoline derivatives to inhibit mitochondrial function, we examined the effects of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (11 isoquinolines, 2 dihydroisoquinolines, and 9 1,2,3,4-tetrahydroisoquinolines) and MPP+ on the enzymes of the respiratory chain in mitochondrial fragments from rat forebrain. With the exception of norsalsolinol and N,n-propylisoquinolinium, all compounds inhibited complex I in a time-independent, but concentration-dependent manner, with IC50s ranging from 0.36-22 mM. Several isoquinoline derivatives were more potent inhibitors of complex I than 1-methyl-4-phenylpyridinium ion (MPP+) (IC50 = 4.1 mM), the most active being N-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.36 mM) and 6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.38 mM). 1,2,3,4-Tetrahydroisoquinoline was the least potent complex I inhibitor (IC50 approximately 22 mM). At 10 mM, only isoquinoline (23.1%), 6,7-dimethoxyisoquinoline (89.6%), and N-methylsalsolinol (34.8%) inhibited (P < 0.05) complex II-III, but none of the isoquinoline derivatives inhibited complex IV. There were no clear structure-activity relationships among the three classes of isoquinoline derivatives studied, but lipophilicity appears to be important for complex I inhibition. The effects of isoquinoline derivatives on mitochondrial function are similar to those of MPTP/MPP+, so respiratory inhibition may underlie their reported neurotoxicity.

The relationship between pH and mRNA preservation in post-mortem human brain was examined using in situ hybridization histochemistry and Northern hybridization with oligonucleotide probes in a large group of human subjects, including control and neuropathological cases. Tissue pH was found to correlate strongly with preservation of four mRNA species in three brain areas. Tissue with low pH, assumed to result from prolonged terminal hypoxia, contained reduced or absent mRNA, while tissue with higher pH was found to contain quantifiable amounts, the values for pathological brain samples being comparable to those for control material of similar pH. Measurement of tissue pH provides a simple means to screen post-mortem brain for mRNA preservation and is suggested as a means to match material in case-control studies of human neurodegenerative disease.

P.M. Rossini (Chairman) (Rome, Baly), A.T. Barker (Sheffield, UK), A. Berardelli (Rome, Italy), M.D. Caramia (Rome, Italy), G. Caruso (Naples, Italy), R.Q. Cracco (Brooklyn, NY;, USA), M.R. Dimitrijevid (Houston, TX, USA), M. Hallett ( Bethesda, MD, USA), Y. Katayama (Tokyo, Japan), C.H. Liicking ( Freiburg, Germany), A.L. Maertens de Noordhout (Liege, Belgium), C.D. Marsden (London, UK), N.M.F. Murray (London, UK), J.C. Rothwell (London, UK), M. Swash (London, UK) and C. Tomberg (Brussels, Belgium)

Groups of patients with idiopathic Parkinson's disease (PD), either medicated or unmedicated, were compared with matched groups of normal controls on a computerised battery of tests designed to investigate spatial working memory, visuospatial recognition memory and learning. The medicated PD patients were subdivided into those with mild and severe clinical disability on the basis of Hoehn and Yahr ratings, thus making three groups of PD patients in all. In a test of spatial recognition memory, a significant impairment was only evident in those PD patients who were medicated and had severe clinical symptoms (Hoehn and Yahr stage III–IV). In contrast, none of the three patient groups were impaired in a complementary test of visual pattern recognition memory. Whilst all three patient groups performed well in a test of simultaneous visual matching to sample, medicated patients (MED PD) with severe clinical symptoms were significantly impaired when a short (0–12 sec) delay was introduced. In a test of paired associates learning requiring both visual pattern and visuospatial memory, deficits in learning and memory were only evident in the severely impaired MED PD group. In contrast, in a test of spatial working memory known to be sensitive to frontal lobe damage, significant impairments were found in both groups of medicated PD patients and particularly in those patients with more severe clinical symptoms. Taken together, the results suggest that there are multiple memory impairments in PD which may differentially depend on the clinical severity of the disease.

The effect of voluntary contraction on the discharge of single motor units following electrical and magnetic stimulation of the motor cortex was examined using the post-stimulus time histogram (PSTH) technique. The latencies of responses in single motor units of the first dorsal interosseous muscle to cortical stimulation were 2-4 msec shorter when the muscle was contracting than when at rest in 9 of 10 units studied. These latency differences are comparable with those recorded by surface electromyography for compound muscle action potentials following cortical stimulation in relaxed and active muscles. The new findings are that the intensity of cortical stimulation required to discharge a resting motor unit to produce a single PSTH peak produced multiple PSTH peaks when the same unit was contracting. The timing of the PSTH peak of relaxed motor unit discharge corresponded to one of the later PSTH peaks (usually the second) when the motor unit was voluntarily activated. These findings are in keeping with our previous suggestions that the longer latency of responses in relaxed muscles is due to the time taken for temporal summation of multiple descending corticospinal volleys at the cortico-motoneurone synapse. Facilitation produced by voluntary contraction occurs at least in part at the level of the spinal cord by lowering motoneurone threshold to enable discharge on the initial descending volley. The higher threshold of relaxed muscles is related to the higher intensities of stimulation needed to recruit multiple descending volleys and discharge resting motoneurones.

Rat brain mitochondria were incubated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its two metabolites (1-methyl-4-phenyl-2,3-dihydropyridium (MPDP+) and 1-methyl-4-phenylpyridinium (MPP+), and O2 uptake was assessed. MPP+ (500 and 1000 microM) inhibited state 3 and state 4 respiration with a reduction in the respiratory control ratio (RCR). In the presence of MPTP or MPDP+ (100-1000 microM) no inhibition of mitochondrial function occurred. Incubation with MPP+ (100-1000 microM) in combination with equimolar concentrations of MPDP+ or MPTP (100-1000 microM) did not increase the inhibition of mitochondrial function produced by MPP+ alone. Inhibition of mitochondrial function produced by MPP+ (500 microM) was not reduced by incorporation of superoxide dismutase (SOD) (50-1000 units/mL). However, the RCR in the presence of 500 microM MPP+ and 1000 units/mL SOD was not different from control values. SOD did not prevent the inhibition of state 3 and state 4 respiration produced by the combination of MPP+ and MPDP+. The results suggest that a redox reaction between MPP+ and MPDP+ to generate superoxide radicals does not contribute to the impairment of mitochondrial function produced by MPTP administration.

Four adult marmosets were treated with increasing doses of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-methyl-MPTP) in the range 0.23-4.3 mg/kg i.p. to give a cumulative dose of 11.0-11.6 mg/kg over a 6-10 day period. After 4 days of treatment, and as the dosage was gradually increased, the animals exhibited mild motor deficits. These abnormalities slowly declined over the following 1-6 week period. In contrast, similar treatment of common marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1-4 mg/kg i.p.) for 3-5 days in a cumulative dose of 6.9-9.2 mg/kg produced gross impairment of motor function which persisted throughout the 5 weeks period of observation. Administration of 2'-methyl-MPTP for 6-10 days caused some decrease in dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), but not homovanillic acid (HVA) content in the caudate nucleus in animals 5-6 weeks after the start of treatment. There was a small decrease in [3H]dopamine uptake into putamen synaptosomes. This contrasted with the marked decreases in all these parameters observed after MPTP treatment of common marmosets. Histological examination of the substantia nigra from the four animals treated with 2'-methyl-MPTP did not show degeneration or loss of dopamine-containing cell bodies in the zona compacta. In contrast, MPTP caused severe destruction of these pigmented nigral neurones. In the common marmoset 2'-methyl-MPTP does not appear to show the same neurotoxic action as MPTP itself. This contrasts with findings in the mouse where 2'-methyl-MPTP is more toxic to dopamine-containing cells of substantia nigra than MPTP.

Thermal injury to one hind limb of rats was induced by immersion into water at 62°C. Both a mild (15 s) or severe (30 s) lesion caused inflammation of the limb when observed 24 h later; but at this time the animals used the injured limb when they walked. Animals with a severe lesion of the injured limb subsequently withdrew it from use when walking. Limb withdrawal did not occur following a mild lesion. At 24 h following the lesion, lumbar spinal cord levels of [Met]enkephalin, as measured by radioimmunoassay, were elevated (70%) bilaterally in both hemisegments, ipsi- and contralateral to the lesion. At seven days following either mild or severe hind limb lesion [Met]enkephalin levels were elevated only in the ipsilateral lumbar hemisegment. At that time no changes in thoracic [Met]enkephalin levels were observed. Substance P levels were decreased (20-25%) bilaterally in the lumbar cord 24 h following a severe limb lesion, but no change was observed at seven days in any cord segment following a mild or severe lesion. Changes in spinal cord [Met]enkephalin content occur in response to thermal injury to one hind limb. However, the changes do not appear to be related to the withdrawal of the damaged limb from use following a severe lesion. Peptide changes in the spinal cord may reflect pain or injury to the damaged limb following a thermal lesion. In contrast, limb withdrawal may be a physiological rest mechanism related to altered basal ganglia peptide function.

From the large body of empirical evidence on cognitive function in Parkinson's disease, a number of attempts have been made to describe the characteristics of the deficits and the conditions under which they are observed. This review considers descriptions limited to specific domains of cognition such as visuospatial function, memory and 'frontal' function, and more general descriptions relating to 'set-shifting', sequencing, temporal ordering and recency discrimination, the locus of cognitive control and bradyphrenia. Later in the paper an attempt is made to provide some theoretical framework for the various descriptions. Two theories are discussed representing contrasting, but complementary approaches. The first is a 'psychological' theory in which the concept of depleted processing resources is suggested as a possible mechanism to explain the observable deficits. The second is a neurobiological model that attempts to integrate information from diverse sources to provide a model for the neuroanatomical and neurochemical substrate that may underlie some of the behavioural deficits.

The present study was performed to determine the effect of a nearly complete nigrostriatal dopaminergic denervation on DARPP-32 levels in the striatum from animals and parkinsonian patients. DARPP-32 levels were estimated by in vitro phosphorylation in the presence of cAMP, or after inactivation of endogenous kinases and phosphatases, in the presence of the catalytic subunit of cAMP-dependent protein kinase. Intranigral 6-hydroxydopamine (6-OHDA) infusion in rats, or peripheral administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to common marmosets, did not change striatal DARPP-32 levels. Postmortem studies, carried out on brains obtained shortly after death, from patients with Parkinson disease, or from patients with progressive supranuclear palsy, showed that the levels of striatal DARPP-32 were not different from controls. These results indicate that dopaminergic striatal denervation did not modify the amount of DARPP-32 in the striatum, suggesting that the expression of DARPP-32, a protein which mediates some of the effects of dopamine in striatal neurons, is independent from the dopaminergic innervation.

The pathological hallmark of Parkinson's disease is cell death of dopaminergic neurons in the substantia nigra, resulting in striatal dopaminergic deficit and a clinical syndrome dominated by disorders of movement. The cause for this cell loss is unknown, but the possibility of a contributing genetic factor is increasingly recognized. Homozygous weaver mice, a mutant mouse strain, display progressive postnatal depletion of dopaminergic cells in the mesencephalon and have thus been proposed as an animal model for Parkinson's disease. Recently, mGIRK2, a putative G-protein inward rectifier K+ channel, has been identified as the causative gene in the weaver mouse and a homozygous mutation has been described in the H5 pore region of this channel. The human homologue of mGIRK2, KCNJ7 or hiGIRK2, has previously been isolated on chromosome 21q22.1. A possible involvement of this gene in the pathogenesis of Parkinson's disease has been discussed. To evaluate the possibility of a shared genetic defect in weaver mouse and Parkinson's disease, we analysed the H5 pore region of hiGIRK2 in familial and sporadic cases of Parkinson's disease. The sequence was normal in all cases examined, suggesting a differing aetiology of nigral cell loss in Parkinson's disease and weaver mice.

Several images of cerebral blood flow were recorded during inhalation of carbon-15-labelled carbon dioxide by positron emission tomography in four patients with essential tremor and four normal controls. Unilateral involuntary postural tremor in essential tremor patients was associated with blood flow significantly greater than that at rest in the contralateral sensorimotor cortex, both lateral premotor regions, and both cerebellar hemispheres. Of these regions, only the cerebellum was not activated in normal controls holding a posture without tremor or in essential tremor patients undergoing passive wrist movement. The increased flow in the cerebellum therefore seems to represent neural activity involved in tremor generation. It is proposed that essential tremor is due to oscillation within cerebello-olivary pathways, relayed by way of the thalamus and motor cortex to the spinal cord.

2but it did not carry the large invasivity plasmid and was rough for its O-antigen. No Shiga toxin producing Ec o l i w e r e detected in the patient’s stool but the S sonnei isolate (named CB7888) showed toxicity to cultured Vero cells and was positive for Stx or Stx1 but negative for Stx2 in a latex agglutination assay (VTEC-RPLA). PCR amplification with primers KS7 and KS8 showed an stx or an s t x1 gene in this s t r a i n . 3 The nucleotide sequence of the entire s t x-gene present in CB7888 was determined (EMBL database, accession AJ132761). The DNA-sequence of the s t xA subunit was found to be completely identical to the sequence of the s t xA subunit found in S dysenteriae type 1 (accession M19437), whereas a one nucleotide difference was found between the coding regions for the s t xB subunit that does not alter the aminoacid residue. 4 An s t x-transducing bacteriophage was isolated from strain CB7888 after mitomycin C induction. The s t x-gene could be transduced by the bacteriophage to s t xnegative reference strains of S sonnei and to a toxin-negative E coli K-12 strain that became lysogenic for the bacteriophage. The lysogenic recipients became positive for production of verocytotoxin and the presence of the s t x-gene in the recipients was shown by PCR. In Shiga-toxin-producing E coli strains, the genes for production of s t x1 and s t x2 are commonly encoded by bacteriophages whereas the s t x-gene of S dysenteriae type 1 is chromosomally located. 5 Production of Stx was only reported for S dysenteriae type 1 5 and to our knowledge this is the first time that a functional s t x-gene was detected in S sonnei. In contrast to S dysenteriae type 1, the s t x-gene of S sonnei w a s found to be encoded by a bacteriophage that is able to transduce the gene to other strains of S sonnei and to E coli K 12. It seems likely that s t x-gene of strain CB7888 originates from S dysenteriae type 1 because the DNA sequences of the two coding regions of the s t xA subunit are identical and differ in three nucleotides from the s t x1A subunit of E coli. It appears thus possible that a transducing Shigella-bacteriophage has mobilised the s t x-gene of S dysenteriae type 1, which has now spread to S sonnei and possibly to other enterobacterial s p e c i e s .

Ever since Kinnier Wilson 8 discovered in 1912 that lesions of the basal ganglia cause abnormal involuntary movements (dyskinesias) in the disease that now bears his name, hepatolenticular degeneration, it has been accepted that the basalganglia are connected with movement, although it is not known how. What exactly is their function? In this review C. D. Marsden examines some recent hypotheses.

Dopamine receptors in the brain play an important role in the treatment of schizophrenia and in the development of tardive dyskinesia. In Parkinson's disease the loss of dopamine innervation and the use of chronic administration of l -DOPA or therapy with dopamine agonists also affects the function of dopamine receptors in brain. Subacute administration of neuroleptic drugs to rodents for a few weeks followed by the withdrawal of the drug induces supersensitivity of dopamine receptors in the striatum. However, the long-term administration of neuroleptic drugs to rodents shows that typical neuroleptic drugs can induce functional supersensitivity of dopamine receptors despite continued administration of drug. In contrast, atypical neuroleptics such as sulpiride, do not appear to induce the same changes in the activity of dopamine receptors. The functional supersensitivity of dopamine receptors produced by repeated administration of neuroleptic is reflected in changes in cholinergic, γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and peptide neuronal systems. Chronic treatment of parkinsonian patients with drugs may obscure the changes in the function of dopamine receptors caused by the disease process. However, chronic administration of l -DOPA to normal rats and to rats with a unilateral lesions of the nigrostriatal pathway induced with 6-hydroxydopamine does not produce a down-regulation of the number of dopamine receptors. Rather, these experiments indicate the development of a functional supersensitivity of dopamine receptors in the absence of any obvious change in the nature of dopamine receptor populations in brain. In conclusion, while pharmacological manipulation, using neuroleptic drugs, produces the expected development of receptor supersensitivity, studies involving chronic treatment with agonists suggests that dopamine receptors do not always respond as would be predicted. It appears that there are aspects of the regulation of dopamine receptors in brain following pharmacological manipulation which remain to be resolved.

The electrolytic brain lesion technique was used to interrupt the ascending serotonergic pathways at the level of the midbrain raphe nuclei in order to determine the role of 5-hydroxytryptamine in the mediation of neuroleptic catalepsy. Lesions of either the medial or dorsal raphe nuclei were shown to reduce the 5-hydroxytryptamine content of the cerebral cortex, striatum and limbic forebrain but had no significant effect on limbic and striatal dopamine levels or on cortical and limbic noradrenaline levels. A differential innervation from the raphe nuclei could not be demonstrated. Lesions of the medial or dorsal raphe nuclei were shown to significantly reduce the cataleptic actions of the neuroleptic agents haloperidol, fluphenazine, oxiperomide and spiroxatrine but had no consistent effect on the cataleptic actions of the dibenzazepine neuroleptics, loxapine and clothiapine. The weak cataleptic action of thioridazine tended to be reduced similarly to that of the classical neuroleptics. The weak effect of clozapine was significantly potentiated by lesions of the dorsal raphe nucleus. The cataleptic effect of the non-neuroleptic agent metoclopramide could not be differentiated from either group of neuroleptics: its actions were reduced by the medial raphe lesions (similarly to the classical neuroleptics), but were not reduced by the dorsal lesions (similarly to the dibenzazepines). The results indicate that 5-hydroxytryptamine function may be important, but not necessarily essential, for the cataleptic action of some neuroleptic agents.

Bilateral injection of apomorphine into the zona reticulata of substantia nigra in rats reduced locomotor activity and striatal dopamine (DA) turnover. In contrast, bilateral injection of (±)-3-(3-hydroxyphenyl)-N, n -propylpiperidine [(±)-3-PPP] into the zona reticulata (ZR) did not reduce locomotor activity and did not affect striatal DA turnover. A high dose of (±)-3-PPP increased locomotor activity. Unilateral injection of (±)-3-PPP, but not of apomorphine, into the ZR induced a brief period of contraversive rotation. (±)-3-PPP may not alter nigral DA autoreceptor function but may interact with DA receptors located on non-dopaminergic nigral neurones.

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to marmosets resulted in parkinsonism and degeneration of the substantia nigra pars compacta. Examination of the hypothalamus showed neuronophagic-like rosettes of glial cells and diffuse increase in glial numbers in areas of the dopaminergic A11-A14 groups. These findings suggest that MPTP may be toxic to dopamine neurons of the hypothalamus as well as to the substantia nigra.

Administration of trifluoperazine (2.5–3.5 mg/kg/day p.o.) or thioridazine (30–40 mg/kg/day) for up to 1 year initially increased homovanillic acid and 3,5-dihydroxyphenylacetic acid cocentrations in striatum. However, by 1 month and thereafter metabolite levels returned to control values. Dopmaine concentrations were elevated after 3 months administrations of both drugs and also after 12 months administration of trifluoperazine Trifluoperzine administration for 1 month produced a marked increase in the dissociation constant (KD) for striatal 3H-spiperone binding but a reduction in receptor numbers. Thereafter receptor numbers increased at 6 and 12 months in both trifluoperazine and thioridazine treated animals compared to control values. The KD for both drug treated groups returned to normal at 6 months; however, by 12 months drug treated animals again demonstrated high KD values. Dopamine stimulation of striatal adenylate cyclase was inhiited after administration of trifluoperazine or thioridazine for 1 week or 1 month. However, by 6 and 12 months this effect was replaced by an enhanced stimulation. Administration of lower doses of trifluoperzine (0.7–0.9 mg/kg/day p.o.) or thioridazine (6–9 mg/kg/day p.o.) for up to 1 year produced similar although generally less marked changes in these biochemical indices of dopamine function. This study provides evidence of biochemical changes which parallel the behavioural findings of enhanced dopamine receptor activity that occur during continuous long-term neuroleptic administration to rodents.

Acute administration of neuroleptic drugs causes blockade of cerebral dopamine receptors. It has been discovered that chronic administration of neuroleptic drugs may have different effects on cerebral dopamine systems. Initial antagonism of dopamine mediated behaviour, such as stereotypy, disappears and may be replaced by supersensitivity to dopamine agonists. Changes also occur in biochemical indices of dopamine receptors, such as in the number and affinity of specific binding sites identified by 3H-ligands labelling D-2 receptors, and in dopamine-stimulated adenylate cyclase activity. All these changes occur obviously in the striatum in response to chronic administration of a range of neuroleptic drugs. Lesser changes take place in the mesolimbic dopamine system. What happens in the mesocortical dopamine pathways is unknown. The consequence of such adaptive responses to chronic neuroleptic therapy may be of importance to understanding of tardive dyskinesia and schizophrenia.

Unilateral electrolytic lesions were made in the areas of the dorsal or the ventral noradrenergic bundles in rats to see if the motor and biochemical effects of unilateral electrolytic locus coeruleus lesions could be reproduced. Lesions of the locus coeruleus result in transient contraversive circling in response to systemically administered apomorphine and d -amphetamine, a transient rise in ipsilateral striatal dopamine and a permanent fall in ipsilateral cerebral cortical noradrenaline. Electrolytic lesions of the dorsal noradrenergic bundle area produced the opposite motor effect, with permanent ipsiversive circling in response to systemically administered apomorphine or d -amphetamine and a reduction in ipselateral cerebral cortical noradrenaline, but no increase in striatal dopamine. Control unilateral electrolytic lesions placed in the adjacent tectum sparing the dorsal bundle area produced neither rotational behaviour nor changes in brain noradrenaline or dopamine levels. Although the damaged area producing ipsiversive rotation included the dorsal noradrenergic bundle, it seems probable that damage to other structures caused this response. Electrolytic lesions of the dorsal bundle did not mimic the effects of electrolytic lesions of the locus coeruleus, and it is unlikely that this ascending pathway carries the fibres responsible for the circling behaviour and changes in striatal dopamine seen with locus coeruleus lesions. Unilateral electrolytic lesions restricted to the ventral noradrenergic bundle caused transient postoperative contraversive circling in response to apomorphine or d -amphetamine, and a transient elevation in the ipsilateral striatal dopamine content; these findings were present 5 days after operation and had disappeared by 1–3 months. Thus lesions of the ventral noradrenergic bundle alone reproduced the effects of lesions of the locus coeruleus. Extension of the lesion to involve the region of the dorsal noradrenergic bundle resulted in ipsiversive rotation in response to systemic apomorphine and d -amphetamine, even though the increase in ipsilateral striatal dopamine content still occurred. It is suggested that the similar findings produced by locus coeruleus and ventral bundle lesions are due to damage to noradrenergic fibres which pass from the locus coeruleus to the nigrostriatal system via the ventral bundle. This proposed pathway is envisaged as normally enhancing nerve impulse flow between the substantia nigra and the striatum. Alternatively, the circling produced by locus coeruleus lesions may be due to secondary alterations in raphe 5-hydroxytryptamine activity, which subsequently affects the nigrostriatal dopamine system.

Only high micromolar concentrations of dopamine and dopamine agonists altered spontaneous and KCl-evoked release of 3H-GABA and 3H-5HT from rat nigral slices in vitro. Apomorphine (100 microM) and dopamine (100 microM) enhanced the spontaneous release of 3H-5HT but the effect of dopamine was not reversed by haloperidol (1 microM). Both apomorphine (100 microM) and dopamine (100 microM) enhanced the KCl-evoked release of 3H-5HT but these effects were not reversed by haloperidol (1 microM). Apomorphine (10-250 microM) and dopamine (10-250 microM) inhibited 3H-5HT uptake into nigral synaptosomal preparations in a concentration-dependent manner. Accordingly, a major portion of the apparent effect of these drugs on 3H-5HT release may be due to inhibition of 3H-5HT uptake. Dopamine (100 and 1000 microM), amphetamine (100 microM), apomorphine (100 microM) and 2-amino-6,7-dihydroxytetralin (ADTN; 100 microM) were without effect on the spontaneous release of 3H-GABA from nigral slices. Apomorphine (100 microM) and ADTN (100 microM) reduced the KCl-evoked release of 3H-GABA from substantia nigra, an effect antagonized by haloperidol (1 microM). However, amphetamine (100 microM) and dopamine (100-1000 microM) were without effect on KCl-evoked 3H-GABA release. These results suggest that only high concentration of some dopamine agonists can modulate 3H-5HT and 3H-GABA release in substantia nigra. However, dopamine either had no effect, or its actions were not reversed by dopamine receptor blockade, so it appears unlikely that dendritic dopamine release will influence GABA and 5HT release in substantia nigra.

Unilateral injections of a putative k - opiate receptor agonist, ethylketocyclazocine, into the globus pallidus of rats caused dose-dependent ipsiversive circling which was inhibited by prior systemic administration of the opiate receptor antagonist naloxone. Neither a putative δ-opiate receptor agonist ([ d -Ala2, d -Leu5]enkephalin) nor a putative μ-opiate receptor agonist (Tyr- d -Ala-Gly-MePhe-Met(0)-ol) induced circling behaviour after unilateral intrapallidal injection. Bilateral intrapallidal injection of the δ-opiate receptor agonist or the μ-opiate receptor agonist caused an increase in locomotor activity which in both cases was reduced by systemic administration of naloxone. A specific δ-receptor antagonist, (N,N-bisalyl-Tyr-Gly-Gly-ψ-(CH2S)-Phe-Leu-OH) had no effect on the increase in locomotor activity caused by the δ-opiate receptor agonist. Bilateral intrapallidal injection of the k - opiate receptor agonist had no effect on locomotor activity. It is suggested that different opiate receptor subtypes within the globus pallidus differentially mediate circling and locomotor behaviour.

We have studied movements of the top joint of the thumb in a group of patients with Parkinson's disease. Even when movements were performed with the proximal phalanx of the thumb clamped, and with the forearm fully supported, movement time was prolonged and multiple bursts of EMG activity were present in the flexor pollicis longus. An abnormality of such movements performed with complete external postural support suggests that disease of the basal ganglia affect all movements, not just those involved in posture.

Bereitschaftspotentials (BPs) prior to extension movements of the index finger were studied in normal subjects and in patients with Parkinson's disease. In both, BPs were studied before and after l -DOPA therapy; in addition, the normal subjects were studied after dopamine antagonists. In both patients and normal subjects, l -DOPA caused an increase in the amplitude of the early part of the BP and of the point of peak negativity, just prior to EMG onset (N1) but it did not cause an increase of the late lateralized part of the BP (NS' of Shibasaki); in normal subjects dopaminergic antagonists caused a decrease in the amplitude of the N1. Control experiments suggested that the change caused by l -DOPA was not the result of slower movement or poorer triggering when OFF drugs. For the patients with Parkinson's diesease there was no correlation between the change in their peak BP negativity (N1) after l -DOPA and their change in clinical mobility; in addition, there was no difference in the peak BP negativity of patients OFF therapy and that of age-matched normals, though there was a slight decrease in the amplitude of the early part of the BP for the patients with Parkinson's disease; this was the same part that had been enlarged by l -DOPA therapy. These findings suggest that the N1 is not affected by Parkinson's disease and that the effect of dopaminergic drugs on the N1 is mediated by actions on dopaminergic mechanisms elsewhere than in the striatum, perhaps in the cerebral cortex itself. The effect of l -DOPA will need to be taken into account in subsequent studies of the BP in Parkinson's disease.

Myoclonus induced in guinea pigs by administration of l -5-hydroxytryptophan (5-HTP) appears to be due to stimulation of central 5-HT receptors. Dose-dependent myoclonus was induced by administration of 5-HTP (with carbidopa pretreatment), l -tryptophan and tryptamine (both with pargyline pretreatment). and also by N , N -dimethyltryptamine, 5-metoxy- N , N -dimethyltryptamine and d -lysergic acid diethylamide (LSD). The synthetic 5-HT agonists quipazine, MK-212 and 1-( m -trifluoromethylphenyl) piperazine, however, evoked only occasional myoclonus at toxic doses. Antagonists of 5-HT receptors differed markedly in their ability to inhibit 5-HTP-induced myoclonus; while methergoline and cyproheptadine were potent inhibitors, mianserin, methysergide and BW 501C67 only caused effective inhibition in large doses. Similarly, 5-HT re-uptake blockers showed different activities in potentiating the effects of a threshold dose of 5-HTP; myoclonus was greatly potentiated by chlorimipramine, paroxetine and Org 6582, while femoxetine, fluoxetine and desmethylimipramine were only weakly active. The lack of uniform effects of the 5-HT agonists, antagonists and re-uptake blockers studied is not attributable entirely to their variable actions on central 5-HT mechanisms, to their effects on other brain neuronal pathways, or to differences in cerebral penetration. The data may provide functional evidence for a multiplicity of cerebral 5-HT receptors.

Fluctuations in performance in patients with Parkinson's disease on chronic levodopa therapy (the "on-off" effect) are due to several factors. The increasing severity during treatment of early morning akinesia, "freezing" episodes, and end-of-dose deterioration are probably due to progression of the underlying disease. Peak-dose dyskinesia and peak-dose akinesia are due to levodopa over-dosage. "Yo-yo-ing", which is the severest form of such fluctuation in mobility and dyskinesias, may represent the sum of these disorders.

Rats with unilateral lesions in the region of the locus coeruleus circled tightly to the opposite side when given apomorphine or amphetamine. This turning behaviour was transient and disappeared within some 30 days after surgery. It was seen most obviously in animals with severe unilateral destruction of the locus coeruleus, which caused on average a 55% reduction in the level of noradrenaline in the ipsilateral cerebral cortex. It was not marked in animals with partial unilateral lesions of the locus coeruleus, which caused only an average fall in cortical noradrenaline of 22%. It was not seen in sham operated animals or animals in which lesions were placed into adjacent structures such as the cerebellum above, superior cerebellar peduncle laterally, and brain stem ventrally. A clue to the mechanism of this phenomenon may lie in the observation that dopamine in the ipsilateral striatum was increased 5 days after operation, when circling occurred, but had returned to normal by 30 days when circling had ceased. It is suggested that the lesion causes a reduction in impulse traffic in the ipsilateral nigrostriatal pathway, and that circling is due to preferential stimulation of the ipsilateral striatal dopamine receptors by both drugs; apomorphine directly, amphetamine by release of endogenous dopamine.

Trifluoperazine dihydrochloride (2.8–4.0 mg/kg/day) was administered continuously to rats in drinking water for six months. Animals killed at this time exhibited an increase in the number of dopamine receptors in the striatum and mesolimbic area, with a corresponding decrease in affinity (increase in the dissociation constant) for 3 H-spiperone binding. In frontal cortex, 3 H-spiperone binding to 5-HT receptors indicated no apparent change in numbers of receptors, but a slight increase in the dissociation constant. There was no obvious alteration in 3 H-apomorphine binding in the striatum and mesolimbic area, but the individual results were very variable. The number and binding affinity of muscarinic receptors in striatum, mesolimbic area and cerebral cortex as identified by 3 H-dexetemide were unchanged. Nor was there any alternation in the number or binding affinity of H-1 receptors identified by 3 H-mepyramine, or of α-noradrenergic receptors identified by 3 H-WB 4101, in cerebral cortex. The number and binding affinity of GABA receptors in the cerebellum identified by 3 H-muscimol also was not altered. Chronic neuroleptic administration to rats appears to alter specifically the number of cerebral dopamine receptors.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), its metabolite 1-methyl-4-phenylpyridine (MPP+) and three analogues of MPTP, lacking an N-methyl moiety, namely, 4-phenylpiperidine (I), 4-phenyl-1,2,3,6-tetrahydropyridine (II) and 4-phenylpyridine (III), were infused continuously for a period of 4 days into the rat substantia nigra. Within 12 h of commencing the bilateral infusion of MPTP or MPP+, rats showed marked motor deficits with reduction in locomotor activity, loss of ability to move the forelimbs and grip with forepaws and, following MPP+ infusions, similar loss of movement in the hindlimbs associated with the development of limb and body rigidity. These motor deficits were not induced by the 3 analogues of MPTP on infusion into the substantia nigra. After 4 days of infusion, the motor deficits caused by MPTP and, in particular, MPP+, were still marked, and for MPP+ these correlated with marked loss of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid. 4-Phenyl-1,2,3,6-tetrahydropyridine caused a small loss in striatal DA and DOPAC, but the other analogues failed to modify the striatal content of DA or its metabolites. Small alterations of chemical structures related to MPTP and its metabolite can critically alter ability to induce behavioural and neurochemical changes reflecting toxicity on the nigrostriatal DA system.

Common marmosets were treated daily with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 7-9 mg/kg i.p.) for 25 days, and then kept out of drug for three months before biochemical measurements in various brain areas. This treatment induced a dramatic fall (-80%) in dopamine, homovanillic acid and dihydroxyphenylacetic acid levels in the putamen and caudate nucleus, and a significant but less pronounced reduction (less than or equal to 50%) in the levels of these compounds in the nucleus accumbens. In contrast, the concentrations of four neuropeptides: met-enkephalin, leu-enkephalin, substance P, and cholecystokinin, remained unaltered in all brain areas examined in MPTP-treated marmosets. Therefore the neuropeptide alterations previously reported in Parkinson's disease are probably not secondary to the severe lesion of dopaminergic neurones, but constitute another intrinsic feature of the disease.

The effect of neuroleptic drugs administered acutely or continuously for 1 year on the release of [ 3 H]glutamate and [ 3 H]acetylcholine from striatal slices in vitro has been compared. Acute in vivo administration of haloperidol, trifluoperazine and clozapine increased the potassium-evoked release of [ 3 H]acetylcholine from striatal slices in a dose-dependent fashion, whereas sulpiride was without effect. None of the neuroleptics given acutely had any effect on the potassium-evoked striatal release of [ 3 H]glutamate. Potassium-evoked striatal release of [ 3 H]acetylcholine in animals receiving 1 year's continuous administration of haloperidol, trifluoperazine or sulpiride was no different from that in age-matched control animals, but was less than controls in animals receiving clozapine for 1 year. All drugs caused a decrease in potassium-evoked striatal [ 3 H]glutamate release following drug administration for 1 year compared to age-matched controls. The reversal of the acute action of neuroleptic drugs on striatal [ 3 H]acetylcholine and [ 3 H]glutamate release is consistent with a functional increase in striatal dopamine transmission following long-term neuroleptic treatment.

The in vivo distribution of radioactivity in brain and labelling of cerebral dopamine receptors in rats derived from the administration of the atypical dopamine agonists [3H]piribedil and [3H]S 3608 has been compared to that of the classical dopamine agonist [3H]N,n-propylnorapomorphine (NPA). Radioactivity derived from [3H]piribedil accumulated in the substantia nigra, nucleus accumbens and cervical spinal cord, and this accumulation was prevented by administration of (+)-butaclamol and apomorphine only in substantia nigra and the nucleus accumbens. Radioactivity derived from [3H]S 3608 accumulated in the same areas and, additionally, in the frontal cortex and tuberculum olfactorium; this accumulation was prevented by administration of (+)-butaclamol and apomorphine only in substantia nigra, nucleus accumbens and tuberculum olfactorium. Neither ligand caused accumulation of radioactivity in the striatum. In contrast, radioactivity derived from [3H]NPA accumulated in the substantia nigra, nucleus accumbens, striatum, and tuberculum olfactorium. Radioactivity derived from [3H]NPA was prevented from accumulating in all these areas by (+)-butaclamol and by apomorphine, but piribedil only prevented accumulation in the substantia nigra and nucleus accumbens and S 3608 only prevented accumulation in substantia nigra, tuberculum olfactorium and nucleus accumbens. Neither piribedil nor S 3608 prevented accumulation of radioactivity derived from [3H]NPA in the striatum. Piribedil and S 3608 showed equal capacity in vitro to displace [3H]spiperone and [3H]NPA from striatal or nucleus accumbens tissue preparations. These results suggest that, in vivo piribedil and S 3608 selectively interact with dopamine receptors in the substantia nigra and nucleus accumbens, but not with those in striatum, perhaps due to differential distribution within brain.

The size of the long-latency component of the stretch reflex has been examined in the time interval between a signal to move and the required rapid voluntary contraction of triceps and flexor pollicis longus in 8 normal subjects. Bilateral movements of the elbow and thumb were made following an auditory signal. In 50% of the trials a torque pulse was applied unilaterally in order to elicit a stretch reflex response in one arm. The voluntary response in the contralateral arm was uncorrupted by a stretch reflex response, so was used as an indicator of voluntary reaction time. Control experiments, using an electrical stimulus to the fingers rather than muscle stretch, verified that both arms reacted almost simultaneously to the auditory cue, even when the reaction time was shortened by the presence of a unilateral electrical stimulus. Similarly, an interposed muscle stretch stimulus considerably reduced the reaction time to the audio signal. Because of this, the start of the voluntary EMG response frequently ‘overlapped’ the end of the long-latency stretch reflex. Failure to take this shortening of voluntary reaction time into consideration can lead to the erroneous conclusion that reflex gain is increased prior to a rapid movement. If the ‘overlap’ of EMG responses is accounted for, very little change in the size of the long-latency stretch reflex is evident prior to activation of the muscles responsible for the movement of either the elbow or the thumb.